1. Field of the Invention
The invention relates to pharmaceutical agents which are cytotoxic in tumor cells. In addition, the invention relates to pharmaceutical agents for use in treating cells which have acquired resistance to chemotherapeutic agents; i.e., cells with multiple drug resistance.
2. History of the Related Art
One of the greatest limitations on the efficacy of cancer chemotherapy is the tendency of cancer cells to develop broad-spectrum resistance to a host of anti-cancer and cytotoxic drugs. Such multiple drug resistance (MDR) is believed to occur to varying degrees in most cancers, either from the onset of the cancer or on recurrence following chemotherapy.
MDR is believed to be mediated by the activity of a cell surface phospho-glycoprotein, P-glycoprotein. Increased expression of the gene which encodes P-glycoprotein (mdr) is found in many malignant cells and may be upregulated by the onset of a malignancy and/or cellular contact with chemotherapeutic agetns. Once active, P-glycoprotein is believed to function as a "hydrophobic vacuum cleaner" which expels hydrophobic drugs from targeted cells. Such drugs include a host of anti-cancer drugs and cytotoxic agents, such as the Vinca alkaloids (e.g., vinblastine), the anthracyclines (e.g., doxorubicin), the epipodophyllotoxins (e.g., etoposide), the taxanes (e.g., taxol), antibiotics (e.g., actinomycin D), antimicrotubule drugs (e.g., colchicine), protein synthesis inhibitors (e.g., puromycin), toxic peptides (e.g., valinomycin), topoisomerase inhibitors (e.g., topotecan), DNA intercalators (e.g., ethidium bromide) and anti-mitotics.
MDR has been the subject of intense research for many years. Efforts to counter MDR have involved the use of hydrophobic competitors for P-glycoprotein binding (such as calcium channel blockers, cephalosporins, steriods, immunosuppressants, antihypertensives, anti-arrhythmics, lipophilic cations, detergents and antidepressants) and tubulin-binding compounds, which inhibit polymerization of membrane-bound microtubulin at sites other than those targeted by antimicrotubule drugs. To varying degrees, most of these competitors eventually fail to sufficiently overcome MDR for reasons including their interference with chemotherapeutic drug uptake, unexpected toxicities and, in the case of the tubulin-binders, tubulin isotype switching.